Gene Responsible for Sensing Mechanical Pain Identified

PainRelief.com Interview with:
Reza Sharif Naeini, Ph.D.
Associate Professor
Department of Physiology & Cell Information Systems Group
McGill University
Life Sciences Complex (Bellini),
Montréal, Québec

PainRelief.com:  What is the background for this study?

Response: My lab is interested in understanding how our bodies detect signals from the environment, like our sense of touch and pain. This process is done by specialized sensors we have that detect mechanical stimuli, ranging from a hair deflecting under the wind, a gentle stroke, or a pinch. These sensors are called mechanosensitive ion channels and they convert mechanical forces into electrical signals that our nervous system can understand.

Their existence was first proposed in 1950 (to my knowledge) by Bernard Katz, and in 1999, researchers at the University of California in San Francisco, led by Dr. Jon Levine, demonstrated that pain-sensing neurons (termed nociceptors) express these channels. But their molecular identity remained elusive.

In 2010, the group of Dr. Ardem Patapoutian discovered the genes Piezo1 and Piezo2, with the latter being essential for our sense of touch and proprioception. While these findings were transformative to the field of somatosensation, mice lacking these genes were still able to respond to painful mechanical stimuli.

PainRelief.com: What are the main findings?

Response: In our study, we identify a gene responsible for our sense of mechanical pain. We show that:

  1. this channel, termed TACAN (movement in Farsi) is expressed in a subset of nociceptors known to respond to mechanical pain. 
  2. When this protein is expressed in cells in culture, it increases their sensitivity to mechanical stimuli. 
  3. When TACAN expression is reduced from nociceptors in culture, they lose their sensitivity to mechanical stimuli.
  4. If we purify TACAN and place it in artificial membranes, it forms an ion channel 
  5. If we let mice grow to become adult, then remove TACAN selectively from nociceptors, the mice lose their capacity to detect/respond to painful mechanical stimuli while remaining sensitive to touch-like stimuli and heat stimuli.

These observations led us to believe that TACAN is essential for the capacity to detect painful mechanical stimuli. Because this ability is so essential to survival, it would not be surprising if there were other ion channels involved in detecting painful mechanical stimuli. 

PainRelief.com: What should readers take away from your report?

Response: That a new target for pain treatment has been identified. And that because this target is expressed in the terminals of pain fibers, targeting it may be possible without the CNS-mediated side effects.

PainRelief.com: What recommendations do you have for future research as a result of this work?

Response: That really depends on the field of study:

In the field of translational (pre-clinical) research, then the next step would be to determine whether the expression of TACAN is affected during chronic pain conditions.

In human genetics, the question would be to determine whether patients with mutations in TACAN have defective pain sensing

In the field of biophysics, then TACAN would be a useful model to determine what are the molecular mechanisms that allow a protein to change its conformation in response to mechanical stimuli. We know how voltage sensing works now, and have some important insights on how temperature sensing works too. But most of our understanding of how channels can sense mechanical stimuli comes from pioneering work done in bacteria. Understanding mammalian mechanotransduction is the next frontier.

PainRelief.com: Is there anything else you would like to add?

Response: Patients suffering from chronic pain see a significant reduction in their quality of lives. They often go on work disability, risk losing their jobs, reduce social interactions, and start developing co-morbidity symptoms such as depression, anxiety. From an economical point of view, the direct and indirect cost associated with chronic pain in Canada alone is an astounding $42 billion/year, higher than those of cancer, heart diseases, and HIV combined. With the rampant problem of opioid overuse that is ongoing right now, there is an urgent need to identify novel targets and develop innovative therapeutic strategies to manage the chronic pain epidemics. We believe the identification of this new sensor will bring give hope of novel pain treatment. 

Citation: Lou Beaulieu-Laroche, Marine Christin, Annmarie Donoghue, Francina Agosti, Noosha Yousefpour, Hugues Petitjean, Albena Davidova, Craig Stanton, Uzair Khan, Connor Dietz, Elise Faure, Tarheen Fatima, Amanda MacPherson, Stephanie Mouchbahani-Constance, Daniel G. Bisson, Lisbet Haglund, Jean A. Ouellet, Laura S. Stone, Jonathan Samson, Mary-Jo Smith, Kjetil Ask, Alfredo Ribeiro-da-Silva, Rikard Blunck, Kate Poole, Emmanuel Bourinet, Reza Sharif-Naeini. TACAN Is an Ion Channel Involved in Sensing Mechanical Pain. Cell, 2020; DOI: 10.1016/j.cell.2020.01.033

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